Project Summary The oral cavity represents a unique healing environment that is relatively unexplored. Regeneration within the oral mucosa occurs rapidly, with wounds closing at four times the rate of the skin, and the inflammatory reaction to wounding is relatively suppressed. Chronic wounds within the oral cavity compromise the ability of patients to obtain nutrition and are prone to debilitating infections, thus constituting an important oral health problem. Understanding how the oral mucosa is able to achieve such regeneration, and therefore how wound healing is disrupted in disease environments, would be a significant achievement for the field of craniofacial research. The specific cellular mechanisms used by the oral mucosa to facilitate its distinct regenerative phenotype remain elusive and are addressed in this proposal. Studies comparing dermal and oral wounds have shown that oral wound healing displays a short inflammatory phase followed by a rapid transition into wound closure via epithelial cell proliferation, migration and differentiation. Chronic inflammation in the oral cavity is the cause of many pathologies, such as periodontitis, oral mucositis and osteonecrosis of the jaw, but how inflammation leads to epithelial atrophy or lingering open wounds in the oral mucosa is unknown. Given that the oral epithelial progenitor cell (OEPC) population mediates re-epithelialization, this proposal will test the hypothesis that inflammation acts as an important coordinator of wound closure and re-epithelialization via direct regulation of the OEPC population. Wound healing will be assessed in animals under three inflammatory states: normal, low and high. The effects of attenuated and exacerbated inflammation on regeneration will be established by scoring for time to wound closure, epithelial layer integrity and proliferation and apoptosis within the entire tissue (Aim 1). Next, the cellular and molecular mechanisms of inflammatory regulation on the OEPC population will be determined using single cell RNA sequencing under the three conditions, and direct regulation of the epithelium by the immune system tested using an in vitro co-culture system (Aim 2). Data from these aims will determine how inflammation regulates wound closure and elucidate key mechanisms through which inflammation influences re-epithelialization, which will yield valuable insights into the mechanisms of wound closure within the oral mucosa. These research goals will be conducted in conjunction with a comprehensive training plan designed to develop the applicant?s career as a dentist-scientist. The training includes structured mentorship from two highly qualified clinician-scientist sponsors, and scientific and technical training through individual and group meetings, seminars, journal clubs, classes and departmental events. Research and training will take place at the University of California, San Francisco, which offers both an outstanding research environment and an excellent dental school for clinical training.